IκB kinase (IKK)-α has been determined for a long time to form a signaling complex with IKKβ and IKKγ that activates nuclear factor-κB (NF-κB). However, emerging evidence demonstrate that it localizes in the nucleus and is a critical regulator for keratinocyte proliferation and differentiation independent of its kinase activity and NF-κB activation. Null mutation of the gene in mice results in hyperproliferation and loss of terminal differentiation of epidermal cells. Reduction of Ikkα expression is also responsible for development and dedifferentiation of squamous cell carcinomas in mice. The role in human carcinoma progression is supported by recent studies that genetic mutation and/or promoter hypermethylation at the IKKα locus is closely associated with dedifferentiation, metastasis and progression of squamous cell carcinomas of the skin and head and heck, and with long-term survival of patients suffering from the diseases. These evidences implicate a fact that IKKα acts as a key molecule for suppression of carcinoma progression. In this review, we discuss on the role in the definition of keratinocyte and carcinoma phenotypes raised by recent studies.
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